Ductal Carcinoma in situ (DCIS)
The analysis of genetic alterations in DCIS has provided new insights in the biology of these lesions. As with invasive carcinoma, abnormalities of chromosomes 1 and 16 have been identified in some of these cases.¹  The comparative genomic hybridisation (CGH) method has been modified for paraffin-embedded material and this has allowed studies on archival material and in particular, the study of preinvasive disease.^2-8  CGH analysis of DCIS has demonstrated a large number of alterations including gains of 1q, 5p, 6q, 8q, 17q, 19q, 20p, 20q, and Xq and losses of 2q, 5q, 6q, 8p, 9p, 11q, 13q, 14q, 16q, 17p, and 22q.^2-8  These alterations are similar to that identified in invasive carcinoma, adding weight to the idea that DCIS is a precursor lesion. Recently, it has been demonstrated that different types of DCIS show different genetic alterations; hence there may be multiple pathways for the evolution of DCIS.^4,6,8,9  Alterations at 16q are much more frequent in low grade DCIS compared to high grade DCIS, in which alterations at 13q, 17q, and 20q are seen more often.^4,6,7,10  Similar findings in invasive carcinomas of low and high grade also support the idea that low grade and high grade lesions develop by separate pathways rather than by de-differentiation.^4,6,7,10  With the use of microdissection techniques to isolate small microscopic lesions, loss of heterozygosity (LOH) has also been investigated in preinvasive disease.^11-17  O'Connell et al¹¹  have carried out studies on preinvasive lesions using a variety of chromosomal markers and showed that 50% of the proliferative lesions and 80% of the DCIS shared their LOH patterns with invasive carcinoma. Stratton et al¹²  studied cases of DCIS associated with invasive carcinoma and cases of 'pure' DCIS without an invasive component using a limited set of microsatellite markers on chromosomes 7q, 16q, 17p and 17q. The study demonstrated a similar frequency of LOH in both subsets of DCIS to invasive carcinoma providing further strong evidence that DCIS is likely to be a precursor of invasive carcinoma. There is considerable support for these early data from a number of other laboratories.^13-20  CerbB2 protein has been identified in a high proportion (60-80%) of DCIS of high nuclear grade (HNG)-comedo-type but is not common in the low nuclear grade (LNG) forms. Allred et al²¹  have shown that the expression is higher in invasive carcinoma associated with DCIS compared to those without DCIS. It is very rarely expressed in LCIS.²²  This gene product has not been identified in benign proliferative disease or ADH.²³  The data suggest that CerbB2 is important in the transition from a 'benign' to 'malignant' phenotype. The different frequency of expression in in situ and invasive carcinoma is a mystery. Either expression is switched off during invasion or many CerbB2 positive DCIS do not transform to invasive malignancy. p53 protein expression has been demonstrated using immunohistochemistry in HNG-DCIS (comedo type).²⁴  The mechanism may be gene mutation but this has only been confirmed in some cases. Like CerbB2, p53 protein expression is rare in LCIS and has not been demonstrated in atypical ductal hyperplasia or other benign proliferative disease.²⁵  Done et al²⁶  demonstrated that p53 mutations found in DCIS and associated invasive cancer were absent from benign proliferative lesions from the same breast. Overall, there is a considerable body of evidence indicating that DCIS, particularly of high grade, shares many molecular genetic alterations with invasive carcinoma and hence is a direct precursor of invasive carcinoma.^4-8,14,15  Moreover, gain of chromosome 1q and loss of 16q which are highly prevalent in low grade DCIS, are frequently found in tubular carcinoma, tubulo-lobular, lobular, and grade 1 invasive ductal carcinomas.^4,6,8,27 

Lobular Carcinoma in situ (LCIS)
Lobular carcinoma in situ of the breast is an uncommon lesion and is composed of discohesive cells with small monomorphic hyperchromatic nuclei. It is usually an incidental finding and is not visible on mammography.²⁸  The majority of the cases are diagnosed between 40-50 years of age, a decade earlier than DCIS. It is also multifocal and bilateral in a high proportion of cases.²⁸  Approximately one fifth of the cases will progress to invasive cancer over a 20-25 year follow up period.²⁸  Although invasive ductal carcinomas, specially of tubular type, do occur after LCIS, most cases associated with LCIS are ILC.²⁸  It has been said that the risk is equal in both breasts,²⁹  however, there are data to suggest that the risk is skewed in favour of the ipsilateral breast.^28,30  Despite this, the features of LCIS have raised questions about the biological nature and it is still generally considered to be "a marker of increased risk" rather than a true precursor of invasive carcinoma. In our laboratories, we have carried out CGH analysis on LCIS and atypical lobular hyperplasia (ALH).³¹  Loss of material from 16p, 16q, 17p and 22q and gain of material from 6q were found at a similar high frequency in both LCIS and ALH. Losses at 1q, 16q, and 17p are also seen in invasive lobular carcinomas.^8,32  LOH data in LCIS are also limited but do demonstrate a similarity between LCIS & ILC.^33,34  E-Cadherin is a candidate tumour suppressor gene on 16q22.1, which is involved in cell-cell adhesion and in cell cycle regulation through b–catenin/Wnt pathway.³⁵  The majority of invasive ductal carcinoma-NST has been shown to exhibit positive staining by immunohistochemistry while most invasive lobular carcinomas are negative.³⁶  Berx et al³⁷  identified protein truncation mutations in 4/7 invasive lobular carcinomas but failed to identify any changes in 42 invasive ductal carcinoma-NST or medullary carcinomas. The mutations in the lobular tumours were accompanied by LOH in the region of the gene and absent staining by immunohistochemistry.

E-Cadherin staining has also been identified in DCIS and the molecule is expressed in normal epithelium but staining is rarely seen in LCIS.^38-43  Recently, some authors have advocated the use of E-cadherin as an adjunct antibody in the differentiation of LCIS from DCIS.^40-43  In addition, Vos et al⁴⁴  have demonstrated the same truncating mutation in the E-Cadherin gene in LCIS and the adjacent invasive lobular carcinoma. The data provide strong evidence for the role of E-Cadherin gene in the pathogenesis of lobular lesions as well as supporting the hypothesis for a precursor role for LCIS. Although E-cadherin germline mutation has been demonstrated in diffuse gastric carcinoma, there is only a single case of lobular carcinoma with germline alteration in the gene.³⁵ 

Atypical Ductal Hyperplasia (ADH)
ADH is a controversial lesion, which shares some but not all features of DCIS. It poses considerable difficulties in surgical histopathology. In order to address this problem, Page & Rogers⁴⁵  laid down criteria for the diagnosis of this entity. Rosai⁴⁶  in his study had demonstrated a high inter-observer variability in the diagnosis of ADH, however, a subsequent study by Schnitt et al,⁴⁷  in which the pathologist used the Page criteria showed an improvement with complete agreement in 58% of cases. Within the UK National Quality Assurance Scheme,⁴⁸  agreement even amongst experienced breast pathologists has been low. Lakhani et al⁴⁹  demonstrated that LOH identified at loci on 16q and 17p in invasive carcinoma and DCIS is also present in ADH with a similar frequency. O'Connell et al¹³  studied 51 cases of ADH at 15 polymorphic loci and found LOH at at least one marker in 42% of the cases. The studies demonstrate that morphological overlaps are reflected at the molecular level and raise questions about the validity of separating ADH from DCIS. CGH analysis of 9 cases of ADH revealed chromosomal abnormalities in 5 of them.⁵⁰  As expected, owing to the morphological overlap with low grade DCIS, losses of 16q and 17p were the most frequent changes found in ADH.⁵⁰ 

Hyperplasia of Usual Type (HUT)
O'Connell et al¹³  have demonstrated that LOH at many different loci can be identified in HUT with frequencies ranging from 0-15%. These figures are similar to those of Lakhani et al⁵¹  who reported data in non-atypical hyperplasia (HUT) dissected from benign breast biopsies. LOH was identified at frequencies ranging from 0% to 13% at locus on 17q. These frequencies are much lower than those identified in DCIS and ADH (range 25-55%). Wasington et al published similar results.⁵²  In their series,⁵⁰  4 of 21 HUTs showed LOH in one to five loci. LOH at 16q (3 cases), 9p (3 cases), and 13q (2 cases) were the most frequent findings.⁵⁰  Although CGH analysis of HUTs has demonstrated that the majority of these lesions harbour no chromosomal abnormalities,^6,50  the picture dramatically changes when they are associated with ADH or DCIS,⁵⁰  In this setting, most lesions show losses of 16q and 17p.⁵⁰  However, it is still premature to accept HUT as a precursor of DCIS and IDC, because in those cases associate with ADH or DCIS, the studies published so far could not exclude the presence of true malignant cells admixed with 'benign' hyperplastic cells of HUTs.

Columnar cell lesions
Columnar cell lesions have been a major source of confusion among breast pathologists, first because they have been reported under several different names, including columnar alteration of lobules, blunt duct adenosis, metaplasie cylindrique, cancerization of small ectatic ducts of the breast by ductal carcinoma in situ cells with apocrine snouts,⁵³  columnar alteration with prominent apical snouts and secretions,⁵⁴  and clinging carcinoma in situ.⁵⁵  These lesions represent a spectrum that ranges from columnar cell alteration in luminal cells to ADH and flat/cliniging DCIS. Regardless of the fact that there are several lines of evidence showing an association with tubular carcinoma,^54,55  only one paper addressed the genetic abnormalities in these lesions.⁵⁵  Moinfar et al⁵⁵  demonstrated that 77% of columnar cell lesions (either with or without atypia) harbour chromosomal abnormalities at least in 1 locus and the most frequent loci of LOH were 11q21-23.2, 16q23.1-24.2, and 3p14.2.⁵⁵  Noteworthy, 16q and 11q are frequently lost in tubular carcinomas.^27,55  More interestingly, these authors⁵⁵  have also shown that otherwise luminal cells with mild nuclear atypia lining ducts at the vicinity of columnar cell lesions may also have loss of genetic material in up to 6% of the cases.

Normal tissues
Over the last few years, seven studies have also demonstrated that LOH identified in invasive carcinoma is already present in morphological normal lobules.^{17,35,52,56,57,58,59}  Lakhani et al⁵⁸  have demonstrated that LOH identified in normal breast epithelial cells is seen independently in luminal and myoepithelial cells, suggesting a common precursor cell for the two epithelial cells. Even more thought provoking is the data published by Moinfar et al,¹⁷  who demonstrated the presence of concurrent and independent genetic alterations in normal appearing stromal and epithelial cells located either at the vicinity or at a distance from the foci of DCIS or IDC. The extent and frequency of alterations and their significance in the multistep carcinogenesis remains unknown at present. It should be noted that in breasts without malignant changes, genetic alterations in normal cells are rather infrequent, subtle and fairly random;⁶  conversely, one paper has demonstrated that normal lobules and adjacent in situ carcinomas show concordant genetic alterations,¹⁷  and other suggested that LOH in normal breast terminal duct lobular units predicts for local recurrence.⁵⁹ 

References:

1. Murphy DS, Hoare SF, Going JJ, Mallon EE, George WD, Kaye SB, Brown R, Black DM, Keith WN: Characterisation of extensive genetic alterations in ductal carcinoma in situ by fluorescence in situ hybridization and molecular analysis. J Natl Cancer Inst 1995, 87: 1694 - 1704.
2. Isola J, DeVries S, Chu L, Ghazvini S, Waldman F: Analysis of changes in DNA sequence copy numbers by coparative genomic hybridization in archival paraffin-embedded tumour samples. Am J Pathol 1994, 145: 1301-1308.
3. Kuukasjarvi T, Tanner M, Pennanen S, Karhu R, Kallioniemi OP, Isola J: Genetic changes in intraductal breast cancer detected by comparative genomic hybridization. Am J Pathol 1997, 150: 1465-71
4. Buerger H, Otterbach F, Simon R, Schafer KL, Poremba C, Diallo R, Brinkschmidt C, Dockhorn-Dworniczak B, Boecker W: Different genetic pathways in the evolution of invasive breast cancer are associated with distinct morphological subtypes. J Pathol1999, 189: 521-6
5. Waldman FM, DeVries S, Chew KL, Moore DH 2nd, Kerlikowske K, Ljung BM: Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences. J Natl Cancer Inst 2000, 92: 313-20.
6. Boecker W, Buerger H, Schmitz K, Ellis IA, van Diest PJ, Sinn HP, Geradts J, Diallo R, Poremba C, Herbst H: Ductal epithelial proliferations of the breast: a biological continuum? Comparative genomic hybridization and high-molecular-weight cytokeratin expression patterns. J Pathol 2001,195: 415-21.
7. Aubele M, Mattis A, Zitzelsberger H, Walch A, Kremer M, Welzl G, Hofler H, Werner M: Extensive ductal carcinoma In situ with small foci of invasive ductal carcinoma: evidence of genetic resemblance by CGH. Int J Cancer 2000, 85: 82-6.
8. Buerger H, Schmidt H, Beckmann A, Zanker KS, Boecker W, Brandt B: Genetic characterisation of invasive breast cancer: a comparison of CGH and PCR based multiplex microsatellite analysis. J Clin Pathol 2001, 54: 836-40.
9. Vos CB, ter Haar NT, Rosenberg C, Peterse JL, Cleton-Jansen AM, Cornelisse CJ, van de Vijver MJ: Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type. Br J Cancer 1999, 81: 1410-8
10. Roylance R, Gorman P, Hanby A, Tomlinson I: Allelic imbalance analysis of chromosome 16q shows that grade I and grade III invasive ductal breast cancers follow different genetic pathways. J Pathol 2002, 196: 32-6
11. O'Connell P, Pekkel V, Fuqua S, Osborne CK, Allred DC: Molecular genetic studies of early breast cancer evolution. Breast Cancer Res Treat 1994, 32: 5-12.
12. Stratton MR, Collins N, Lakhani SR, Sloane JP: Loss of heterozygosity in ductal carcinoma in situ of the breast. J Pathol 1995, 175: 195-201.
13. O'Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC: Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 1998, 90: 697-703.
14. Shen CY, Yu JC, Lo YL, Kuo CH, Yue CT, Jou YS, Huang CS, Lung JC, Wu CW: Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. Cancer Res 2000, 60: 3884-92.
15. Farabegoli F, Champeme MH, Bieche I, Santini D, Ceccarelli C, Derenzini M, Lidereau R: Genetic pathways in the evolution of breast ductal carcinoma in situ. J Pathol 2002, 196: 280-6.
16. Regitnig P, Moser R, Thalhammer M, Luschin-Ebengreuth G, Ploner F, Papadi H, Tsybrovskyy O, Lax SF: Microsatellite analysis of breast carcinoma and corresponding local recurrences. J Pathol 2002, 198: 190-7.
17. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA: Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 2000, 60: 2562-6.
18. Fujii H, Szumel R, Marsh C, Zhou W, Gabrielson E: Genetic progression, histological grade, and allelic loss in ductal carcinoma in situ of the breast. Cancer Res 1996, 56: 5260-5.
19. Koreth J, Bethwaite PB, McGee JOD: Mutations at chromosome 11q23 in human non-familial breast cancer: a microdissection microsatellite analysis. J Pathol 1995, 176: 11-18.
20. Marcello Aldaz C, Chen T, Sahin A, Cunningham J, Bondy M: Comparative allelotype of in situ and invasive humanbreast cancer: High frequency of microsatellite instability in lobular breast carcinoma. Cancer Res 1995, 55: 3976-3981.
21. Allred DC, Clark GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW, Osborne CK, Tormey DC, McGuire WL: Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 1992, 23: 974-9.
22. Gusterson BA, Machin LG, Gullick WJ, Gibbs NM, Powles TJ, Price P, McKinna A, Harrison S: Immunohistochemical distribution of c-erbB-2 in infiltrating and in situ breast cancer. Int J Cancer 1988, 42: 842-5.
23. Gusterson BA, Machin LG, Gullick WJ, Gibbs NM, Powles TJ, Elliott C, Ashley S, Monaghan P, Harrison S: c-erbB-2 expression in benign and malignant breast disease. Br J Cancer 1988, 58: 453-7.
24. Poller DN, Roberts EC, Bell JA, Elston CW, Blamey RW, Ellis IO: p53 protein expression in mammary ductal carcinoma in situ: relationship to immunohistochemical expression of estrogen receptor and c-erbB-2 protein. Hum Pathol 1993, 24: 463-8.
25. Allred DC, O'Connell P, Fuqua SA, Osborne CK: Immunohistochemical studies of early breast cancer evolution. Breast Cancer Res Treat 1994, 32: 13-8.
26. Done SJ, Arneson NC, Ozcelik H, Redston M, Andrulis IL: p53 mutations in mammary ductal carcinoma in situ but not in epithelial hyperplasias. Cancer Res 1998, 58: 785-9.
27. Buerger H, Otterbach F, Simon R, Schafer KL, Poremba C, Diallo R, Brinkschmidt C, Dockhorn-Dworniczak B, Boecker W: Different genetic pathways in the evolution of invasive breast cancer are associated with distinct morphological subtypes. J Pathol 1999, 189: 521-6.
28. Lishman SC, Lakhani SR: Atypical lobular hyperplasia and lobular carcinoma in situ: surgical and molecular pathology. Histopathology 1999, 35: 195-200.
29. Goldschmidt RA, Victor TA: Lobular carcinoma in situ of the breast. Semin Surg Oncol 1996, 12: 314-20.
30. Etzell JE, Devries S, Chew K, Florendo C, Molinaro A, Ljung BM, Waldman FM: Loss of chromosome 16q in lobular carcinoma in situ. Hum Pathol 2001, 32: 292-6.
31. Lu YJ, Osin P, Lakhani SR, Di Palma S, Gusterson BA, Shipley JM: Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia. Cancer Research 1998, 5820: 4721-7
32. Nishizaki T, Chew K, Chu L, Isola J, Kallioniemi A, Weidner N, Waldman FM: Genetic alterations in lobular breast cancer by comparative genomic hybridization. Int J Cancer 1997, 74: 513-7.
33. Lakhani S, Collins N, Sloane J, Stratton M: Loss of heterozygosity in lobular carcinoma in situ of the breast. J Clin Pathol: Mol Pathol 1995, 48: M74-M78.
34. Nayar R, Zhuang Z, Merino MJ, Silverberg SG: Loss of heterozygosity on chromosome 11q13 in lobular lesions of the breast using tissue microdissection and polymerase chain reaction. Hum Pathol 1997, 28: 277-82.
35. Keller G, Vogelsang H, Becker I, Hutter J, Ott K, Candidus S, Grundei T, Becker KF, Mueller J, Siewert JR, Hofler H: Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am J Pathol 1999, 155: 337-42.
36. Peralta Soler A, Knudsen KA, Salazar H, Han AC, Keshgegian AA: P-cadherin expression in breast carcinoma indicates poor survival. Cancer 1999, 86: 1263-72.
37. Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C, van Roy F: E-Cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J 1995, 14: 6107-6115.
38. Gamallo C, Palacios J, Suarez A, Pizarro A, Navarro P, Quintanilla M, Cano A: Correlation of E-cadherin expression with differentiation grade and histological type in breast carcinoma. Am J Pathol 1993, 142: 987-93.
39. Rasbridge SA, Gillett CE, Sampson SA, Walsh FS, Millis RR: Epithelial (E-) and placental (P-) cadherin cell adhesion molecule expression in breast carcinoma. J Pathol 1993, 169: 245-50.
40. Jacobs TW, Pliss N, Kouria G, Schnitt SJ: Carcinomas in situ of the breast with indeterminate features: role of E-cadherin staining in categorization. Am J Surg Pathol 2001, 25: 229-36.
41. Maluf HM, Swanson PE, Koerner FC: Solid low-grade in situ carcinoma of the breast: role of associated lesions and E-cadherin in differential diagnosis. Am J Surg Pathol 2001, 25: 237-44.
42. Bratthauer GL, Moinfar F, Stamatakos MD, Mezzetti TP, Shekitka KM, Man YG, Tavassoli FA: Combined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal, and hybrid mammary intraepithelial neoplasias. Hum Pathol 2002, 33: 620-7.
43. Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP: Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol 2002, 15: 1044-50.
44. Vos CB, Cleton-Jansen AM, Berx G, de Leeuw WJ, ter Haar NT, van Roy F, Cornelisse CJ, Peterse JL, van de Vijver MJ: E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 1997, 76: 1131-3.
45. Page DL, Rogers LW: Combined histologic and cytologic criteria for the diagnosis of mammary atypical ductal hyperplasia. Hum Pathol 1992, 23: 1095-7.
46. Rosai J: Borderline epithelial lesions of the breast. Am J Surg Pathol 1991, 15: 209-21.
47. Schnitt SJ, Connolly JL, Tavassoli FA, Fechner RE, Kempson RL, Gelman R, Page DL: Interobserver reproducibility in the diagnosis of ductal proliferative breast lesions using standardized criteria Am J Surg Pathol 1992, 16: 1133-43.
48. Sloane JP, Ellman R, Anderson TJ, Brown CL, Coyne J, Dallimore NS, Davies JD, Eakins D, Ellis IO, Elston CW: Consistency of histopathological reporting of breast lesions detected by screening: findings of the U.K. National External Quality Assessment (EQA) Scheme. Eur J Cancer 1994, 30A: 1414-1419.
49. Lakhani SR, Collins N, Stratton MR, Sloane JP: Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. J Clin Pathol 1995, 48: 611-5
50. Gong G, DeVries S, Chew KL, Cha I, Ljung BM, Waldman FM: Genetic changes in paired atypical and usual ductal hyperplasia of the breast by comparative genomic hybridization. Clin Cancer Res 2001, 7: 2410-4.
51. Lakhani S, Slack D, Hamoudi R, Collins N, Stratton M, Sloane J: Detection of alleleic imbalance indicates that a proportion of mammary hyperplasia of usual type are clonal, neoplastic proliferations. Lab Invest 1996, 74: 129-135.
52. Washington C, Dalbegue F, Abreo F, Taubenberger JK, Lichy JH: Loss of heterozygosity in fibrocystic change of the breast: genetic relationship between benign proliferative lesions and associated carcinomas. Am J Pathol 2000, 157: 323-9.
53. Goldstein NS, O'Malley BA: Cancerization of small ectatic ducts of the breast by ductal carcinoma in situ cells with apocrine snouts: a lesion associated with tubular carcinoma. Am J Clin Pathol 1997, 107: 561-6.
54. Fraser JL, Raza S, Chorny K, Connolly JL, Schnitt SJ: Columnar alteration with prominent apical snouts and secretions: a spectrum of changes frequently present in breast biopsies performed for microcalcifications. Am J Surg Pathol 1998, 22: 1521-7.
55. Moinfar F, Man YG, Bratthauer GL, Ratschek M, Tavassoli FA: Genetic abnormalities in mammary ductal intraepithelial neoplasia-flat type ("clinging ductal carcinoma in situ"): a simulator of normal mammary epithelium. Cancer 2000, 88: 2072-81.
56. Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS: Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 1996, 274: 2057-9.
57. Larson PS, de las Morenas A, Cupples LA, Huang K, Rosenberg CL: Genetically abnormal clones in histologically normal breast tissue 7. Am J Pathol 1998, 152: 1591-8.
58. Lakhani SR, Chaggar R, Davies S, Jones C, Collins N, Odell C, Stratton MR, O'Hare M: Loss of heterozygosity (LOH) in normal luminal and myoepithelial cells of the breast. J Pathol 1999, 189: 496-503.
59. Li Z, Moore DH, Meng ZH, Ljung BM, Gray JW, Dairkee SH: Increased risk of local recurrence is associated with allelic loss in normal lobules of breast cancer patients. Cancer Res 2002, 62: 1000-1003.